Hematopoietic stem cells (HSC) in aging mice preferentially lose the ability to regenerate the adaptive immune system. This skewing towards production of myeloid cells and other HSC abnormalities may contribute to the immunosenescence seen in humans. That is, the quality of responses to vaccination can be poor or inappropriate in aged individuals. The circumstances that elicit these changes and the underlying mechanisms are largely unknown. While HSC are harmed by chemotherapy, radiation, DNA repair defects, loss of telomerase and elevated cytokines, selective loss of lymphopoietic potential has not been reported in those circumstances. In contrast, we have found myeloid skewing, defective self-renewal and other age-related changes in HSC recovered from mice repeatedly exposed to very low doses of lipopolysaccharide. This is despite the fact that the animals were in generally good health and numbers of HSC were normal. These remarkable findings suggest that persistent low-grade infections and associated pathogen products might cause HSC senescence and ultimately compromise immunity. It is possible that similar HSC changes are caused by endogenous Toll- like receptor (TLR) ligands associated with tissue damage and obesity. We will now determine if the phenomenon occurs with other TLR ligands and in an animal model of inflammatory bowel disease (IBD). Additionally, we will explore the means through which HSC are harmed. The findings are expected to be informative about normal aging as well as many chronic conditions such as HIV/AIDS that may accelerate immunosenescence. Also, a basis may be found for age-related shifts in patterns of some hematopoietic malignancies.